Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D1R Radioligand [11C]SCH23390 in Healthy and Diseased Mice

Daniele Bertoglio; Jeroen Verhaeghe; Alan Miranda; Leonie Wyffels; Sigrid Stroobants; Celia Dominguez; Ignacio Munoz-Sanjuan; Mette Skinbjerg; Longbin Liu; Steven Staelens

doi:10.1007/s11307-020-01561-1

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D₁R Radioligand [¹¹C]SCH23390 in Healthy and Diseased Mice

Mol Imaging Biol. 2021 Apr;23(2):208-219. doi: 10.1007/s11307-020-01561-1. Epub 2020 Nov 11.

Authors

Affiliations

¹ Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium.
² Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
³ CHDI Management/CHDI Foundation, Los Angeles, CA, USA.
⁴ Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium. steven.staelens@uantwerpen.be.

Abstract

Purpose: Our aim in this study was to compare different non-invasive pharmacokinetic models and assess test-retest reproducibility of the radioligand [¹¹C]SCH23390 for the quantification of dopamine D₁-like receptor (D₁R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington's disease (HD) model.

Procedures: Adult WT (n = 9) and HET (n = 14) mice underwent a 90-min [¹¹C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [¹¹C]SCH23390 PET scan for test-retest reproducibility. Parallel assessment of the simplified reference tissue model (SRTM), the multilinear reference tissue model (MRTM) and the Logan reference tissue model (Logan Ref) using the striatum as a receptor-rich region and the cerebellum as a receptor-free (reference) region was performed to define the most suitable method for regional- and voxel-based quantification of the binding potential (BP_ND). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement.

Results: For all models, we measured a significant decline in dopamine D₁R density (e.g. SRTM = - 38.5 ± 5.0 %, p < 0.0001) in HET mice compared to WT littermates. Shortening the 90-min scan duration resulted in large underestimation of striatal BP_ND in both WT mice (SRTM 60 min: - 17.7 ± 2.8 %, p = 0.0078) and diseased HET (SRTM 60 min: - 13.1 ± 4.1 %, p = 0.0001). Striatal BP_ND measurements were very reproducible with an average test-retest variability below 5 % when using both MRTM and SRTM. Parametric BP_ND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r² = 0.99, p < 0.0001). Finally, SRTM provided the most accurate estimate for relative tracer delivery R₁ with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BP_ND (r² < 0.66).

Conclusions: Ninety-minute acquisition and the use of SRTM for pharmacokinetic modelling is recommended. [¹¹C]SCH23390 PET imaging demonstrates optimal characteristics for the study of dopamine D₁R density in models of psychiatric and neurological disorders as exemplified in the Q175DN mouse model of HD.

Keywords: D1R; Dopamine receptor; Huntington’s disease; Kinetic modelling; Mouse; Preclinical imaging; Q175DN; SCH23390; Test-retest.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzazepines / pharmacokinetics*
Brain / diagnostic imaging*
Brain / metabolism
Carbon Radioisotopes
Disease Models, Animal
Gene Knock-In Techniques
Huntington Disease / diagnostic imaging*
Huntington Disease / metabolism
Huntington Disease / pathology
Male
Mice
Mice, Transgenic
Molecular Imaging / methods*
Positron-Emission Tomography / methods*
Receptors, Dopamine D1 / antagonists & inhibitors*
Receptors, Dopamine D1 / metabolism
Reproducibility of Results
Tissue Distribution

Substances

Benzazepines
Carbon Radioisotopes
Carbon-11
Receptors, Dopamine D1
SCH 23390